ABSTRACT
Nanoscale-diameter liquid droplets from commercially available microbubbles may optimize thrombus permeation and subsequent thrombus dissolution (TD). Thrombi were made using fresh porcine arterial whole blood and placed in an in vitro vascular simulation. A diagnostic ultrasound probe in contact with a tissue-mimicking phantom tested intermittent high-mechanical-index (HMI) fundamental multipulse (focused ultrasound [FUS], 1.8 MHz) versus harmonic single-pulse (HUS, 1.3 MHz) modes during a 10-min infusion of Definity nanodroplets (DNDs), Definity microbubbles (DMBs) or saline. The ability of FUS and intravenous DNDs to improve epicardial and microvascular flow was then tested in four pigs with left anterior descending thrombotic occlusion. Sixty in vitro thrombi were tested, 20 in each group. Percentage TD was significantly higher for DND-treated thrombi than DMB-treated thrombi and controls (DNDs: 42.4%, DMBs: 26.7%, saline: 15.0%; p < 0.0001 vs. control). The highest %TD was seen in the HMI FUS-treated DND group (51 ± 17% TD). HMI FUS detected droplet activation within the risk area in three of four pigs with left anterior descending thrombotic occlusion and re-canalized the epicardial vessel in two. DNDs with intermittent diagnostic HMI ultrasound resulted in significantly more intravascular TD than DMBs and have potential for coronary and risk area thrombolysis.
Subject(s)
Contrast Media , Fluorocarbons , Mechanical Thrombolysis/methods , Microbubbles , Nanostructures , Thrombosis/therapy , Ultrasonic Therapy/methods , Acoustics , Animals , Phantoms, Imaging , SwineABSTRACT
We sought to explore mechanistically how intermittent high-mechanical-index (MI) diagnostic ultrasound impulses restore microvascular flow. Thrombotic microvascular obstruction was created in the rat hindlimb muscle of 36 rats. A diagnostic transducer confirmed occlusion with low-MI imaging during an intravenous microbubble infusion. This same transducer was used to intermittently apply ultrasound with an MI that produced stable or inertial cavitation (IC) for 10 min through a tissue-mimicking phantom. A nitric oxide inhibitor, L-Nω-nitroarginine methyl ester (L-NAME), was pre-administered to six rats. Plateau microvascular contrast intensity quantified skeletal microvascular blood volume, and postmortem staining was used to detect perivascular hemorrhage. Intermittent IC impulses produced the greatest recovery of microvascular blood volume (p < 0.0001, analysis of variance). Nitric oxide inhibition did not affect the skeletal microvascular blood volume improvement, but did result in more perivascular hemorrhage. IC inducing pulses from a diagnostic transducer can reverse microvascular obstruction after acute arterial thromboembolism. Nitric oxide may prevent unwanted bio-effects of these IC pulses.
Subject(s)
Microvessels , Peripheral Arterial Disease/therapy , Thromboembolism/therapy , Ultrasonography/methods , Animals , Disease Models, Animal , Rats , Rats, Sprague-DawleyABSTRACT
The purpose of this study was to determine whether high mechanical index (MI) impulses from diagnostic ultrasound (DUS) could dissolve intravascular thrombi using intravenous microbubbles. Using a canine model, DUS was applied during a continuous intravenous infusion of microbubbles. Completely thrombosed grafts were assigned to 2 treatment regimens: low-MI (<0.5-MI) ultrasound alone; or intermittent high-MI impulses (1.9-MI) guided by low-MI ultrasound (contrast pulse sequencing). A 20-MHz cavitation detector was placed confocal to the ultrasound transducer to make intravascular cavitation measurements in 1 dog. Intravascular cavitational activity was detected when an MI of >0.5 was applied. In grafts treated with intermittent high-MI ultrasound, angiographic success was 71% at 30 min and 79% at 45 min, compared with 20% and 30% at these times in the low-MI ultrasound alone group (p < 0.05). We conclude that a commercially available DUS transducer can successfully recanalize acute intravascular thrombi during a continuous microbubble infusion.
